Aicardi–Goutières syndrome (AGS) is a rare autoimmune neurological disorder belonging to type I interferonopathies.
There are seven subtypes based on the different pathogenic genes: three prime repair exonuclease 1 (TREX1) (AGS1), RNASEH2B (AGS2), RNASEH2C (AGS3), RNASEH2A (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6) and IFIH1 (AGS7).
Mutations affecting RNASEH2B and TREX1 are reported to be the most common, representing 35% and 17% of all cases, respectively.
AGS is usually inherited in an autosomal recessive manner. However, there may also be de novo or inherited autosomal dominant pathogenic variants in TREX1 or ADAR, as well as heterozygous autosomal dominant pathogenic variants in IFIH1. Mutations in the above genes affect the targeting and/or metabolism of nucleic acids, thereby promoting a type I interferon (IFN-I)-mediated innate immune response.
AGS was first described by Jean Aicardi and Francoise Goutières in 1984 with a case series of eight children from five families with severe early-onset encephalopathy.
The major clinical features of AGS include encephalopathy, significant intellectual disability, acquired microcephaly during the first year of life, dystonia, spasticity, sterile pyrexias, intracranial calcifications, white matter lesions, brain atrophy, bilateral striatal necrosis, chilblain lesions on the feet, hands, ears or more diffuse throughout the skin.
The characteristic features include lymphocytosis, high levels of interferon α (IFN-α) in the cerebrospinal fluid (CSF) and serum with an increased expression of interferon-stimulated genes (ISGs) in the peripheral blood—the so-called “interferon signature”.
Patients may also have intracerebral vasculopathy, hepatosplenomegaly, elevated liver enzymes, thrombocytopenia, hemolytic anemia, elevated autoantibodies, hypothyroidism, insulin-dependent diabetes mellitus, transitory antidiuretic hormone deficiency, neonatal cardiomyopathy and demyelinating peripheral neuropathy.
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In the most severe form, this condition features microcephaly, leukodystrophy, cerebral atrophy, intracranial calcifications, along with hepatosplenomegaly and thrombocytopenia. It is associated with elevated levels of central nervous system type I interferon signaling and often progresses with severe neurologic symptoms and death in early childhood. However, milder forms may show later onset with features of a lupus-like syndrome including painful skin lesions and congenital glaucoma.
AGS is often mistaken for TORCH (Toxoplasmosis, Others, Rubella, Cytomegalovirus, Herpes) infections.
Ocular manifestations include glaucoma (congenital or later onset), optic atrophy, and cortical blindness.
Most cases of glaucoma are diagnosed within the first 6 months of life. Studies have shown that the risk of glaucoma development differs depending on the specific genetic mutation. In a study of AGS, glaucoma was diagnosed in 6.3%, of which 20.8% were patients with a pathological SAMHD1. The ADAR and IFIH1 mutations were found to be the least associated with glaucoma.
Congenital glaucoma can be considered as a part of the phenotypic spectrum of AGS; therefore, regular ophthalmological examinations are essential, especially in the first years of a child’s life, in order to diagnose the disease and promptly initiate treatment.
